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Expert Review of Anti-infective Therapy Mar 2021Tecovirimat (TPOXX®; ST-246) was approved for the treatment of symptomatic smallpox by the USFDA in July of 2018 and has been stockpiled by the US government for use in... (Review)
Review
INTRODUCTION
Tecovirimat (TPOXX®; ST-246) was approved for the treatment of symptomatic smallpox by the USFDA in July of 2018 and has been stockpiled by the US government for use in a smallpox outbreak. While there has not been a reported case of smallpox since 1978 it is still considered a serious bioterrorism threat.
AREAS COVERED
A brief history of smallpox from its proposed origins as a human disease through its eradication in the late 20th century is presented. The current smallpox threat and the current public health response plans are described. The discovery, and development of tecovirimat through NDA submission and subsequent approval for treatment of smallpox are discussed. Google Scholar and PubMed were searched over all available dates for relevant publications.
EXPERT OPINION
Approval of tecovirimat to treat smallpox represents an important milestone in biosecurity preparedness. Incorporating tecovirimat into the CDC smallpox response plan, development of pediatric liquid and intravenous formulations, and approval for post-exposure prophylaxis would provide additional health security benefit.Tecovirimat shows broad efficacy against orthopoxviruses in vitro and in vivo and could be developed for use against emerging orthopoxvirus diseases such as monkeypox, vaccination-associated adverse events, and side effects of vaccinia oncolytic virus therapy.
Topics: Antiviral Agents; Benzamides; Bioterrorism; Humans; Isoindoles; Orthopoxvirus; Poxviridae Infections; Smallpox
PubMed: 32882158
DOI: 10.1080/14787210.2020.1819791 -
Epidemics Sep 2019Many pathogens of conservation concern circulate endemically within natural wildlife reservoir hosts and it is imperative to understand the individual and ecological...
Many pathogens of conservation concern circulate endemically within natural wildlife reservoir hosts and it is imperative to understand the individual and ecological drivers of natural transmission dynamics, if any threat to a related endangered species is to be assessed. Our study highlights the key drivers of infection and shedding dynamics of squirrelpox virus (SQPV) in its reservoir grey squirrel (Sciurus carolinensis) population. To clarify SQPV dynamics in this population, longitudinal data from a 16-month mark-recapture study were analysed, combining serology with real-time quantitative PCR to identify periods of acute viraemia and chronic viral shedding. At the population level, we found SQPV infection prevalence, viral load and shedding varied seasonally, peaking in autumn and early spring. Individually, SQPV was shown to be a chronic infection in >80% of grey squirrels, with viral loads persisting over time and bouts of potential recrudescence or reinfection occurring. A key recurring factor significantly associated with SQPV infection risk was the presence of co-infecting squirrel adenovirus (ADV). In dual infected squirrels, longitudinal analysis showed that prior ADV viraemia increased the subsequent SQPV load in the blood. However, there was a strong, negative association between prior ADV viraemia and subsequent SQPV shedding from the forearm, probably caused by ADV prolonging the SQPV acute viraemic phase, so delaying onset of the chronic shedding phase, and thereby altering viral shedding patterns over the time scales examined here. Hence, co-circulating ADV infection may be involved in mediating both the quantitative levels of SQPV infection and the timing and degree of subsequent infectiousness of grey squirrels.
Topics: Animals; Poxviridae Infections; Prevalence; Sciuridae; Seasons; Viral Load
PubMed: 31327730
DOI: 10.1016/j.epidem.2019.100352 -
Journal of Virology Feb 2017Myxomatosis is a recurrent problem on rabbit farms throughout Europe despite the success of vaccines. To identify gene variations of field and vaccine strains that may...
UNLABELLED
Myxomatosis is a recurrent problem on rabbit farms throughout Europe despite the success of vaccines. To identify gene variations of field and vaccine strains that may be responsible for changes in virulence, immunomodulation, and immunoprotection, the genomes of 6 myxoma virus (MYXV) strains were sequenced: German field isolates Munich-1, FLI-H, 2604, and 3207; vaccine strain MAV; and challenge strain ZA. The analyzed genomes ranged from 147.6 kb (strain MAV) to 161.8 kb (strain 3207). All sequences were affected by several mutations, covering 24 to 93 open reading frames (ORFs) and resulted in amino acid substitutions, insertions, or deletions. Only strains Munich-1 and MAV revealed the deletion of 10 ORFs (M007L to M015L) and 11 ORFs (M007L to M008.1L and M149R to M008.1R), respectively. Major differences were observed in the 27 immunomodulatory proteins encoded by MYXV. Compared to the reference strain Lausanne, strains FLI-H, 2604, 3207, and ZA showed the highest amino acid identity (>98.4%). In strains Munich-1 and MAV, deletion of 5 and 10 ORFs, respectively, was observed, encoding immunomodulatory proteins with ankyrin repeats or members of the family of serine protease inhibitors. Furthermore, putative immunodominant surface proteins with homology to vaccinia virus (VACV) were investigated in the sequenced strains. Only strain MAV revealed above-average frequencies of amino acid substitutions and frameshift mutations. Finally, we performed recombination analysis and found signs of recombination in vaccine strain MAV. Phylogenetic analysis showed a close relationship of strain MAV and the MSW strain of Californian MYXV. However, in a challenge model, strain MAV provided full protection against lethal challenges with strain ZA.
IMPORTANCE
Myxoma virus (MYXV) is pathogenic for European rabbits and two North American species. Due to sophisticated strategies in immune evasion and oncolysis, MYXV is an important model virus for immunological and pathological research. In its natural hosts, MYXV causes a benign infection, whereas in European rabbits, it causes the lethal disease myxomatosis. Since the introduction of MYXV into Australia and Europe for the biological control of European rabbits in the 1950s, a coevolution of host and pathogen has started, selecting for attenuated virus strains and increased resistance in rabbits. Evolution of viruses is a continuous process and influences the protective potential of vaccines. In our analyses, we sequenced 6 MYXV field, challenge, and vaccine strains. We focused on genes encoding proteins involved in virulence, host range, immunomodulation, and envelope composition. Genes affected most by mutations play a role in immunomodulation. However, attenuation cannot be linked to individual mutations or gene disruptions.
Topics: Amino Acid Substitution; Animals; Ankyrin Repeat; Apoptosis; Cell Line; Chlorocebus aethiops; Evolution, Molecular; Genetic Variation; Genome, Viral; Genomics; Immunomodulation; Inflammation; Leukocytes; Mutation; Myxoma virus; Open Reading Frames; Phylogeny; Poxviridae Infections; Protein Binding; Protein Interaction Mapping; Rabbits; Receptors, Immunologic; Viral Proteins; Viral Vaccines
PubMed: 27903800
DOI: 10.1128/JVI.01570-16 -
Immunological Reviews Jan 2011The eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively... (Review)
Review
The eradication of smallpox, one of the great triumphs of medicine, was accomplished through the prophylactic administration of live vaccinia virus, a comparatively benign relative of variola virus, the causative agent of smallpox. Nevertheless, recent fears that variola virus may be used as a biological weapon together with the present susceptibility of unimmunized populations have spurred the development of new-generation vaccines that are safer than the original and can be produced by modern methods. Predicting the efficacy of such vaccines in the absence of human smallpox, however, depends on understanding the correlates of protection. This review outlines the biology of poxviruses with particular relevance to vaccine development, describes protein targets of humoral and cellular immunity, compares animal models of orthopoxvirus disease with human smallpox, and considers the status of second- and third-generation smallpox vaccines.
Topics: Animals; Antibodies, Viral; Biological Warfare Agents; Disease Models, Animal; Gene Expression Regulation, Viral; Humans; Mice; Orthopoxvirus; Poxviridae Infections; Smallpox; Smallpox Vaccine; Vaccines; Vaccinia virus; Variola virus
PubMed: 21198662
DOI: 10.1111/j.1600-065X.2010.00975.x -
The Journal of Veterinary Medical... Sep 2010To date, several DNA viral infections have been reported in psittacine birds. Psittacine beak and feather disease (PBFD) is characterized by symmetric feather dystrophy... (Review)
Review
To date, several DNA viral infections have been reported in psittacine birds. Psittacine beak and feather disease (PBFD) is characterized by symmetric feather dystrophy and loss and development of beak deformities. PBFD is caused by beak and feather virus, which belongs to the Circoviridae, and is the most important infection in psittacine birds worldwide. Avian polyomavirus infection causes acute death, abdominal distention, and feather abnormalities. Pacheco's disease (PD), which is caused by psittacid herpesvirus type 1, is an acute lethal disease without a prodrome. Psittacine adenovirus infections are described as having a clinical progression similar to PD. The clinical changes in psittacine poxvirus-infected birds include serious ocular discharge, rhinitis, and conjunctivitis, followed by the appearance of ulcerations on the medial canthi of the eyes. Internal papillomatosis of parrots (IPP) is a tumor disease characterized by progressive development of papillomas in the oral and cloacal mucosa. IPP has been suggested to caused by papillomavirus or herpesvirus. However, information about these diseases is limited. Here we review the etiology, clinical features, pathology, epidemiology, and diagnosis of these DNA viruses.
Topics: Adenoviridae Infections; Animals; Beak; Bird Diseases; Circoviridae Infections; DNA Viruses; DNA, Viral; Feathers; Herpesviridae Infections; Papillomavirus Infections; Polyomavirus Infections; Poxviridae Infections; Psittaciformes; Virus Diseases
PubMed: 20424393
DOI: 10.1292/jvms.10-0022 -
FEMS Microbiology Reviews Apr 2000Because they were the largest of all viruses and could be visualised with a light microscope, the poxviruses were the first viruses to be intensively studied in the... (Review)
Review
Because they were the largest of all viruses and could be visualised with a light microscope, the poxviruses were the first viruses to be intensively studied in the laboratory. It was clear from an early date that they caused important diseases of humans and their domestic animals, such as smallpox, cowpox, camelpox, sheeppox, fowlpox and goatpox. This essay recounts some of the early history of their recognition and classification and then expands on aspects of research on poxviruses in which the author has been involved. Studies on the best-known genus, Orthopoxvirus, relate to the use of infectious ectromelia of mice as a model for smallpox, embracing both experimental epidemiology and pathogenesis, studies on the genetics of vaccinia virus and the problem of non-genetic reactivation (previously termed 'transformation') and the campaign for the global eradication of smallpox. The other group of poxviruses described here, the genus Leporipoxvirus, came to prominence when the myxoma virus was used for the biological control of Australian wild rabbits. This provided a unique natural experiment on the coevolution of a virus and its host. Future research will include further studies of the many immunomodulatory genes found in all poxviruses of vertebrates, since these provide clues about the workings of the immune system and how viruses have evolved to evade it. Some of the many recombinant poxvirus constructs currently being studied may come into use as vaccines or for immunocontraception. A field that warrants study but will probably remain neglected is the natural history of skunkpox, raccoonpox, taterapox, yabapox, tanapox and other little-known poxviruses. A dismal prospect is the possible use of smallpox virus for bioterrorism.
Topics: Animals; History, 20th Century; Humans; Mice; Poxviridae; Poxviridae Infections; Rabbits; Research; Vertebrates
PubMed: 10717311
DOI: 10.1016/S0168-6445(00)00027-9 -
Viruses Dec 2020The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of... (Review)
Review
The global emergence of zoonotic viruses, including poxviruses, poses one of the greatest threats to human and animal health. Forty years after the eradication of smallpox, emerging zoonotic orthopoxviruses, such as monkeypox, cowpox, and vaccinia viruses continue to infect humans as well as wild and domestic animals. Currently, the geographical distribution of poxviruses in a broad range of hosts worldwide raises concerns regarding the possibility of outbreaks or viral dissemination to new geographical regions. Here, we review the global host ranges and current epidemiological understanding of zoonotic orthopoxviruses while focusing on orthopoxviruses with epidemic potential, including monkeypox, cowpox, and vaccinia viruses.
Topics: Animals; Geography, Medical; Host Specificity; Humans; Orthopoxvirus; Poxviridae Infections; Viral Zoonoses
PubMed: 33396609
DOI: 10.3390/v13010043 -
Viruses Mar 2023Mpox, formerly called monkeypox, is now the most serious orthopoxvirus (OPXV) infection in humans. This zoonotic disease has been gradually re-emerging in humans with an... (Review)
Review
Mpox, formerly called monkeypox, is now the most serious orthopoxvirus (OPXV) infection in humans. This zoonotic disease has been gradually re-emerging in humans with an increasing frequency of cases found in endemic areas, as well as an escalating frequency and size of epidemics outside of endemic areas in Africa. Currently, the largest known mpox epidemic is spreading throughout the world, with over 85,650 cases to date, mostly in Europe and North America. These increased endemic cases and epidemics are likely driven primarily by decreasing global immunity to OPXVs, along with other possible causes. The current unprecedented global outbreak of mpox has demonstrated higher numbers of human cases and greater human-to-human transmission than previously documented, necessitating an urgent need to better understand this disease in humans and animals. Monkeypox virus (MPXV) infections in animals, both naturally occurring and experimental, have provided critical information about the routes of transmission; the viral pathogenicity factors; the methods of control, such as vaccination and antivirals; the disease ecology in reservoir host species; and the conservation impacts on wildlife species. This review briefly described the epidemiology and transmission of MPXV between animals and humans and summarizes past studies on the ecology of MPXV in wild animals and experimental studies in captive animal models, with a focus on how animal infections have informed knowledge concerning various aspects of this pathogen. Knowledge gaps were highlighted in areas where future research, both in captive and free-ranging animals, could inform efforts to understand and control this disease in both humans and animals.
Topics: Animals; Humans; Monkeypox virus; Animals, Wild; Mpox (monkeypox); Zoonoses; Poxviridae Infections; Models, Animal
PubMed: 37112885
DOI: 10.3390/v15040905 -
Philosophical Transactions of the Royal... May 2018Provision of supplementary food for wild birds at garden feeding stations is a common, large-scale and year-round practice in multiple countries including Great Britain... (Review)
Review
Provision of supplementary food for wild birds at garden feeding stations is a common, large-scale and year-round practice in multiple countries including Great Britain (GB). While these additional dietary resources can benefit wildlife, there is a concomitant risk of disease transmission, particularly when birds repeatedly congregate in the same place at high densities and through interactions of species that would not normally associate in close proximity. Citizen science schemes recording garden birds are popular and can integrate disease surveillance with population monitoring, offering a unique opportunity to explore inter-relationships between supplementary feeding, disease epidemiology and population dynamics. Here, we present findings from a national surveillance programme in GB and note the dynamism of endemic and emerging diseases over a 25-year period, focusing on protozoal (finch trichomonosis), viral (Paridae pox) and bacterial (passerine salmonellosis) diseases with contrasting modes of transmission. We also examine the occurrence of mycotoxin contamination of food residues in bird feeders, which present both a direct and indirect (though immunosuppression) risk to wild bird health. Our results inform evidence-based mitigation strategies to minimize anthropogenically mediated health hazards, while maintaining the benefits of providing supplementary food for wild birds.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'.
Topics: Animal Feed; Animals; Bird Diseases; Epidemiological Monitoring; Humans; Immunity, Innate; Mycotoxins; Passeriformes; Population Dynamics; Poxviridae Infections; Risk Factors; Salmonella Infections; Trichomonas Infections; United Kingdom
PubMed: 29531146
DOI: 10.1098/rstb.2017.0091 -
Cells Dec 2023Conventional dendritic cells (cDCs) are innate immune cells that play a pivotal role in inducing antiviral adaptive immune responses due to their extraordinary ability...
Conventional dendritic cells (cDCs) are innate immune cells that play a pivotal role in inducing antiviral adaptive immune responses due to their extraordinary ability to prime and polarize naïve T cells into different effector T helper (Th) subsets. The two major subpopulations of cDCs, cDC1 (CD8α in mice and CD141 in human) and cDC2 (CD11b in mice and CD1c in human), can preferentially polarize T cells toward a Th1 and Th2 phenotype, respectively. During infection with ectromelia virus (ECTV), an orthopoxvirus from the family, the timing and activation of an appropriate Th immune response contributes to the resistance (Th1) or susceptibility (Th2) of inbred mouse strains to the lethal form of mousepox. Due to the high plasticity and diverse properties of cDC subpopulations in regulating the quality of a specific immune response, in the present study we compared the ability of splenic cDC1 and cDC2 originating from different ECTV-infected mouse strains to mature, activate, and polarize the Th immune response during mousepox. Our results demonstrated that during early stages of mousepox, both cDC subsets from resistant C57BL/6 and susceptible BALB/c mice were activated upon in vivo ECTV infection. These cells exhibited elevated levels of surface MHC class I and II, and co-stimulatory molecules and showed enhanced potential to produce cytokines. However, both cDC subsets from BALB/c mice displayed a higher maturation status than that of their counterparts from C57BL/6 mice. Despite their higher activation status, cDC1 and cDC2 from susceptible mice produced low amounts of Th1-polarizing cytokines, including IL-12 and IFN-γ, and the ability of these cells to stimulate the proliferation and Th1 polarization of allogeneic CD4 T cells was severely compromised. In contrast, both cDC subsets from resistant mice produced significant amounts of Th1-polarizing cytokines and demonstrated greater capability in differentiating allogeneic T cells into Th1 cells compared to cDCs from BALB/c mice. Collectively, our results indicate that in the early stages of mousepox, splenic cDC subpopulations from the resistant mouse strain can better elicit a Th1 cell-mediated response than the susceptible strain can, probably contributing to the induction of the protective immune responses necessary for the control of virus dissemination and for survival from ECTV challenge.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Ectromelia, Infectious; Poxviridae Infections; Cytokines; Dendritic Cells
PubMed: 38201217
DOI: 10.3390/cells13010013